DIANE-35 PILLS (PACK)

Dosage / Direction for Use: 1 tab daily at the same time each day for 21 days starting on 1st day of mens followed by 7 tab-free days. Overdosage: There have been no reports of serious deleterious effects from overdose. Symptoms that may occur in this case are: nausea, vomiting and, in young girls, slight vaginal bleeding. There are no antidotes and further treatment should be symptomatic. Administration: May be taken with or without food. Contraindications: Hypersensitivity. Presence or history of venous or arterial thrombotic/thromboembolic events (eg, DVT, pulmonary embolism, MI) or CVA; prodromi of thrombosis (eg, transient ischaemic attack, angina pectoris); migraine w/ focal neurological symptoms; pancreatitis associated w/ severe hypertriglyceridemia; liver tumors. Severe or multiple risk factors for venous or arterial thrombosis. DM w/ vascular involvement. Known or suspected sex steroid-influenced malignancies (eg, of the genital organs & breasts); undiagnosed vag bleeding. Severe hepatic disease. Pregnancy & lactation. Warnings: The clinical and epidemiological experience with estrogen/progestogen combinations like Cyproterone acetate + Ethinylestradiol (Diane-35) is predominantly based on combined oral contraceptives (COC). Therefore, the following warnings related to the use of COC apply also for Cyproterone acetate + Ethinylestradiol (Diane-35). If any of the conditions/risk factors mentioned as follows is present, the benefits of use of Cyproterone acetate + Ethinylestradiol (Diane-35) should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using it. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether use of Cyproterone acetate + Ethinylestradiol (Diane-35) should be discontinued. Circulatory Disorders: Epidemiological studies have suggested an association between the use of COCs and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, deep venous thrombosis, pulmonary embolism and of cerebrovascular accidents. These events occur rarely. The risk of VTE is highest during the first year of use. This increased risk is present after initially starting a COC or restarting (following a 4 week or greater pill free interval) the same or a different COC. Data from a large, prospective 3-armed cohort study suggest that this increased risk is mainly present during the first 3 months. Overall the risk for venous thromboembolism (VTE) in users of low estrogen dose (<50 μg ethinylestradiol) COCs is two to threefold higher than for non-users of COCs who are not pregnant and remains lower than the risk associated with pregnancy and delivery. VTE may be fatal (in 1-2% of the cases). Venous thromboembolism (VTE), manifesting as deep venous thrombosis and/or pulmonary embolism, may occur during the use of all COCs. Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of COCs. Symptoms of deep venous thrombosis (DVT) can include: unilateral swelling of the leg or along a vein in the leg; pain or tenderness in the leg which may be felt only when standing or walking, increased warmth in the affected leg; red or discolored skin on the leg. Symptoms of pulmonary embolism (PE) can include: sudden onset of unexplained shortness of breath or rapid breathing; sudden coughing which may bring up blood; sharp chest pain which may increase with deep breathing; sense of anxiety; severe light headedness or dizziness; rapid or irregular heartbeat. Some of these symptoms (e.g. "shortness of breath", "coughing") are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections). An arterial thromboembolic event can include cerebrovascular accident, vascular occlusion or myocardial infarction (MI). Symptoms of a cerebrovascular accident can include: sudden numbness or weakness of the face, arm or leg, especially on one side of the body; sudden confusion, trouble speaking or understanding; sudden trouble seeing in one or both eyes; sudden trouble walking, dizziness, loss of balance or coordination; sudden, severe or prolonged headache with no known cause; loss of consciousness or fainting with or without seizure. Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity; acute abdomen. Symptoms of MI can include: pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone; discomfort radiating to the back, jaw, throat, arm, stomach; fullness, indigestion or choking feeling; sweating, nausea, vomiting or dizziness; extreme weakness, anxiety, or shortness of breath; rapid or irregular heartbeats. Arterial thromboembolic events may be fatal. The risk of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident increases with: age; obesity (body mass index over 30 kg/m2); a positive family history (i.e. venous or arterial thromboembolism ever in a sibling or parent at a relatively early age). If a hereditary predisposition is known or suspected, the woman should be referred to a specialist for advice before deciding about any COC use; prolonged immobilization, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue COC use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilization; smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age); dyslipoproteinemia; hypertension; migraine; valvular heart disease; atrial fibrillation. There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism. The increased risk of thromboembolism in the puerperium must be considered (for information on pregnancy and lactation see Use in Pregnancy & Lactation). Other medical conditions which have been associated with adverse circulatory events include diabetes mellitus, polycystic ovary syndrome, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease. An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC. Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include Activated Protein C (APC) resistance, hyperhomocysteinemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant). When considering risk/benefit, the physician should take into account that adequate treatment of a condition may reduce the associated risk of thrombosis and that the risk associated with pregnancy is higher than that associated with low-dose COCs (<0.05 mg ethinylestradiol). Tumors: The most important risk factor for cervical cancer is persistent HPV infection. Some epidemiological studies have indicated that long-term use of COCs may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g., cervical screening and sexual behaviour including use of barrier contraceptives. A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR=1.24) of having breast cancer diagnosed in women who are currently using COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users. In rare cases, benign liver tumors, and even more rarely, malignant liver tumors have been reported in users of COCs. In isolated cases, these tumors have led to life-threatening intra-abdominal hemorrhages. A liver tumor should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal hemorrhage occur in women taking COCs. Other conditions: Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs. Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the physician to withdraw the COC and treat the hypertension. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy. The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss. In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs. Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using low-dose COCs (containing <0.05 mg ethinylestradiol). However, diabetic women should be carefully observed while taking COCs. Crohn's disease and ulcerative colitis have been associated with COC use. Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking COCs. If in women suffering from hirsutism, symptoms have recently developed or increased substantially, the causes (androgen-producing tumor, adrenal enzyme defect) must be clarified by differential diagnosis. Each coated tablet of this medicinal product contains 31 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet should take this amount into consideration. Special Precautions: Increased risk of arterial & venous thrombotic & thromboembolic diseases eg, MI, DVT, pulmonary embolism & of CVA. Venous thromboembolism manifesting as DVT &/or pulmonary embolism may occur during therapy. Consider the risk of thromboembolism in the puerperium. Conditions associated w/ circulatory events include DM, polycystic ovary syndrome, SLE, hemolytic uremic syndrome, Crohn's disease or ulcerative colitis & sickle cell disease. Discontinue in case of increase in frequency or severity of migraine. Increased risk of tumor in long-term use. Women w/ or history of hypertriglyceridemia may be at risk of pancreatitis when using COCs; women w/ hereditary angioedema exogenous estrogens; diabetic women Discontinue in case of acute or chronic disturbances of liver function. Women w/ history of chloasma gravidarum; women w/ tendency to chloasma should avoid exposure to the sun or UV radiation while taking COCs. Rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet. Irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the 1st mth of use. Use In Pregnancy & Lactation: Pregnancy: Cyproterone acetate + Ethinylestradiol (Diane-35) is not indicated during pregnancy. If pregnancy occurs during treatment with Cyproterone acetate + Ethinylestradiol (Diane-35), further intake must be stopped (see Pharmacology: Toxicology: Preclinical safety data under Actions). Lactation: The administration of Cyproterone acetate + Ethinylestradiol (Diane-35) is contraindicated during lactation. Cyproterone acetate is transferred into the milk of lactating women. About 0.2% of the maternal dose will reach the newborn via milk corresponding to a dose of about 1 μg/kg. 0.02% of the daily maternal dose of ethinylestradiol could be transferred to the newborn via milk during established lactation. Caution for Usage: Instructions for use/handling: None. Incompatibilities: None. Side Effects / Adverse Reactions: Nausea, abdominal pain, wt increased; headache, depressed or altered mood; breast tenderness or pain Interactions: Breakthrough bleeding &/or contraceptive failure w/ enzyme inducers or some antibiotics. Increased clearance of sex hormones w/ drugs that induce microsomal enzymes (eg, phenytoin, barbiturates, primidone, carbamazepine, rifampicin & possibly oxcarbazepine, topiramate, felbamate, griseofulvin & St. John's wort). Potentially increased hepatic metabolism w/ HIV protease (eg, ritonavir) & non-nucleoside reverse transcriptase inhibitors (eg, nevirapine). Decreased enterohepatic circulation (which may reduce conc) w/ penicillins & tetracyclines. Increased plasma & tissue conc w/ cyclosporin. Decreased plasma & tissue conc w/ lamotrigine. Mechanism of Action: Pharmacology: Pharmacodynamics: The pilosebaceous unit - consisting of the sebaceous gland and the hair follicle - is an androgen-sensitive skin component. Acne, seborrhea, hirsutism and androgenetic alopecia are clinical conditions resulting from aberrations of this target organ which may be caused by increased sensitivity or higher plasma levels of androgen. Both substances contained in Cyproterone acetate + Ethinylestradiol (Diane-35) influence beneficially the hyperandrogenic state: Cyproterone acetate is a competitive antagonist on the androgen receptor, has inhibitory effects on the androgen-synthesis in target cells and produces a decrease of the androgen blood concentration through an antigonadotropic effect. This antigonadotropic effect is amplified by ethinylestradiol which up-regulates as well the synthesis of Sexual-Hormone-Binding-Globulin (SHBG) in plasma. It thereby reduces free, biologically available androgen in the circulation. A large, prospective 3-armed cohort study has shown that the frequency of VTE diagnosis ranges between 8 to 10 per 10,000 woman years in low estrogen dose (<50 μg ethinylestradiol) COC users. The most recent data suggest that the frequency of VTE diagnosis is approximately 4.4 per 10,000 woman years in non-pregnant non-COC users, and ranges between 20 to 30 per 10,000 pregnant women or post partum. Treatment with Cyproterone acetate + Ethinylestradiol (Diane-35) leads - usually after 3 to 4 months of therapy - to the healing of existing acne efflorescences. The excessive greasiness of the hair and skin generally disappears earlier. The loss of hair which frequently accompanies seborrhea likewise diminishes. In women experiencing mild forms of hirsutism and, in particular, slightly increased facial hair, results do not, however, become apparent until after several months of use. The contraceptive effect of Cyproterone acetate + Ethinylestradiol (Diane-35) is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the cervical secretion. In addition to protection against pregnancy, estrogen/progestogen combinations have - besides adverse properties (see Warnings and Adverse Reactions) - positive properties: The cycle is more regular and the menstruation is often less painful and bleeding is lighter. The latter may result in a decrease in the occurrence of iron deficiency. Pharmacokinetics: Cyproterone acetate: Absorption: Orally administered cyproterone acetate is rapidly and completely absorbed. Peak serum concentrations of 15 ng/ml are reached at about 1.6 hours after single ingestion. Bioavailability is about 88%. Distribution: Cyproterone acetate is almost exclusively bound to serum albumin. Only 3.5-4.0% of the total serum drug concentrations are present as free steroid. The ethinylestradiol-induced increase in SHBG does not influence the serum protein binding of cyproterone acetate. The apparent volume of distribution of cyproterone acetate is about 986±437 l. Metabolism: Cyproterone acetate is almost completely metabolized. The main metabolite in plasma was identified as 15β-OH-CPA which is formed via the cytochrome P450 enzyme CYP3A4. The clearance rate from serum is about 3.6 ml/min/kg. Elimination: Cyproterone acetate serum levels decrease in two phases which are characterized by half-lives of about 0.8 h and about 2.3-3.3 days. Cyproterone acetate is partly excreted in unchanged form. Its metabolites are excreted at a urinary to biliary ratio of about 1:2. The half-life of metabolite excretion is about 1.8 days. Steady-state conditions: Cyproterone acetate pharmacokinetics are not influenced by SHBG levels. Following daily ingestion drug serum levels increase about 2.5-fold reaching steady-state conditions during the second half of a treatment cycle. Ethinylestradiol: Absorption: Orally administered ethinylestradiol is rapidly and completely absorbed. Peak serum concentrations of about 71 pg/ml are reached at 1.6 hours. During absorption and first-liver passage, ethinylestradiol is metabolized extensively, resulting in a mean oral bioavailability of about 45% with a large interindividual variation of about 20-65%. Distribution: Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98%), and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 2.8-8.6 l/kg was determined. Metabolism: Ethinylestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolized by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucuronides and sulfate. The clearance rate was reported to be about 2.3-7 ml/min/kg. Elimination: Ethinylestradiol serum levels decrease in two disposition phases characterized by half-lives of about 1 hour and 10-20 hours, respectively. Unchanged drug is not excreted, ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is about 1 day. Steady-state conditions: Steady-state conditions are reached during the second half of a treatment cycle when serum drug levels are higher by 60% as compared to single dose. Toxicology: Preclinical safety data: Ethinyl estradiol: The toxicity profile of ethinyl estradiol is well known. There are no preclinical data of relevance to the prescriber that provide additional safety information to those already included in other sections of the product information. Cyproterone acetate: Systemic toxicity: Preclinical data reveal no specific risk for humans based on conventional studies of repeated dose toxicity. Embryotoxicity/teratogenicity: Investigations into embryotoxicity using the combination of the two active ingredients showed no effects indicative of a teratogenic effect following treatment during organogenesis before development of the external genital organs. Administration of cyproterone acetate during the hormone-sensitive differentiation phase of the genital organs led to signs of feminization in male fetuses following higher doses. Observation of male newborn children who had been exposed in utero to cyproterone acetate did not show any signs of feminization. However, pregnancy is a contraindication for the use of Cyproterone acetate + Ethinylestradiol (Diane-35). Genotoxicity and carcinogenicity: Recognized first-line tests of genotoxicity gave negative results when conducted with cyproterone acetate. However, further tests showed that cyproterone acetate was capable of producing adducts with DNA (and an increase in DNA repair activity) in liver cells from rats and monkeys and also in freshly isolated human hepatocytes, the DNA-adduct level in dog liver cells was extremely low. This DNA-adduct formation occurred at systemic exposures that might be expected to occur in the recommended dose regimens for cyproterone acetate. In vivo consequences of cyproterone acetate treatment were the increased incidence of focal, possibly pre-neoplastic, liver lesions in which cellular enzymes were altered in female rats, and an increase of mutation frequency in transgenic rats carrying a bacterial gene as target for mutations. Clinical experience and well conducted epidemiological trials to date would not support an increased incidence of hepatic tumors in man. Nor did investigations into the tumorigenicity of cyproterone acetate in rodents reveal any indication of a specific tumorigenic potential. However, it must be borne in mind that sexual steroids can promote the growth of certain hormone-dependent tissues and tumors. On the whole, the available findings do not raise any objection to the use of Cyproterone acetate + Ethinylestradiol (Diane-35) in humans if used in accordance with the directions for the given indication and at the recommended dose.